Choroidal neovascularization (CNV) refers to the uncontrolled growth of choroidal vasculature which can lead to severe vision loss in diseases such as pseudoxanthoma elasticum, angioid streaks, histoplasmosis, punctuate inner choroidopathy and wet age related macular degeneration (AMD). Wet AMD occurs when the deposition of drusen (complement components, lipids, and apolipoproteins) causes confined ischemic regions resulting in hypoxia. It is believed that hypoxia leads to an increase in the secretion of vascular endothelial growth factor (VEGF), which activates choroidal endothelial cells to secrete matrix metalloproteinases (MMP). Metalloproteinases degrade the extracellular matrix, thereby allowing for the proliferation of endothelial cells and their migration towards the retina. The effect of MMP eventually results in the development of new blood vessels, or CNV, which can cause retinal detachment and hemorrhage and the formation of sub retinal lesions due to blood and lipid leakage. Once manifested, CNV is a major cause of vision loss in the elderly population of industrialized nations.
Treatment of CNV is currently limited to a fraction of the patient population and focuses on restraining the detrimental role of VEGF in vascular hyperpermeability and new blood vessel formation. However, VEGF also plays a constructive key role in physiological activities such as wound healing, photoreceptor survival, and maintaining the choroid capillary bed. Currently, Ranibizumab (Lucentis™), Aflibercept (Eylea™) and pegaptanib (Macugen™) are the only two therapeutic agents that have been approved to date to treat CNV. These agents inhibit VEGF. It has been shown that ranibizumab is generally more effective than pegaptanib in treating CNV. Ranibizumab binds to all isoforms of VEGF-A and inhibits VEGF activity including vascular permeability and growth. Other than the two mentioned therapeutic agent, bevacizumab (Avastin™), the parent full length antibody of ranibizumab, is also being explored as an off label treatment for CNV.
Despite the success of these therapies in treating CNV there are inherent drawbacks in these therapies, including lack of apoptosis in activated endothelial cells, and potential impairment of VEGF related physiological activities such as wound healing. In addition, use of ranibizumab leads to systemic risks including increased rate of thromboembolic events after intravitreal administration in humans. Intravitreal bevacizumab has also been associated with ischemic attack, blood pressure elevation, cerebrovascular accidents, and death. Further, in a clinical trial with patients suffering from CNV, the response rate to ranibizumab was only ˜40% in patients with CNV and the gain in number of letters was only 7.2.
Therefore, there is a need for new and/or more effective therapeutic approach for treating CNV that has reduced side effects and/or better therapeutic efficacy.